DESCRIPTION: Neuronal ceroid lipofuscinosis (NCL) is a group of hereditary, autosomal recessive, degenerative brain diseases that are characterized by the accumulation of lipid storage bodies resembling pigments that form with advanced age in normal tissues. The most severe form, infantile NCL (INCL) is caused by defects in a lysosomal enzyme, palmitoyl-protein thioesterase (PPT). This enzyme removes covalently-attached fatty acids from cystein residues in proteins. The defective lysosomal thioesterase activity leads to the accumulation of small, protein-derived, cystein lipid thioesters in infantile NCL cells. The final result is neuronal degeneration and clinical "brain death" by the age of 3 years in most patients. INCL is most prevalent in the Finnish population where a single point mutation in PPT accounts for 40/42 cases. The incidence of PPT deficiency among NCL patients outside of Finland is unknown. A major goal of this proposal is to determine the frequency of PPT deficiency in the US. NCL population and to define the unique characteristics of these patients. Furthermore, mutations in the PPT gene will be characterized in PPT-deficient subjects and correlated the clinical phenotype. The information gained from the study of naturally-occurring mutations will be used to explore structure-function relationships in the PPT enzyme. Finally, the role of a PPT homolog (PPT-2) will be investigated in NCL and other neurodegenerative diseases.